Left ventricular (LV) dysfunction, once established, worsens over time, despite the absence of intercurrent adverse events. This LV deterioration often culminates in congestive heart failure (HF). The mechanisms responsible for this process are not fully understood. We and others have speculated that progression of LV dysfunction and subsequent transition to over HF may be due, in part, to progressive global LV remodeling, and the cellular level, to ongoing loss of cardiomyocytes and/or progressive worsening of intrinsic contractile dysfunction of residual myocytes. During the past funding cycle, we showed for the first time, that progressive LV dysfunction and dilation are accompanied by ongoing loss of viable myocardium. Pioneering studies by us in dogs with HF and by others, in end-stage, explanted failed human hearts, evoked cardiomyocyte apoptosis, as a potential cause of ongoing loss of viable myocardium in HF. While critical to our knowledge of the overall pathophysiology of HF, the true importance of these findings is tempered by the existence of a major gap in our understanding of the adaptations and/or maladaptations, inherent to the HF state, that drive the process of ongoing cardiac muscle cell death that ultimately leads to intractable HF. In this application, we propose new investigations intended to close this knowledge gap. Over the next 5 years, we propose to determine if a relationship exists between 1) the severity of LV dysfunction and the extent of cardiomyocyte apoptosis; 2) progression of LV dysfunction and the activity and expression of protein phosphatases; enzymes that have been suggested to promote apoptosis and have been shown by us to be elevated in HF; and 3) the severity of LV dysfunction and susceptibility of cardiomyocytes to undergo apoptosis mediated by norepinephrine, angiotensin-II and hypoxia; all of which are classic features of HF. We further propose to examine if in-vivo treatment of HF with vascular endothelial growth factor ameliorates the hypoxic state through angiogenesis and, in doing so, prevent hypoxia-mediated apoptosis and, consequently, prevent the progression to overt HF. Finally, we will address the role of a central adaptation in HF namely, whether the process of progressive LV dilation itself promotes cardiomyocyte loss or vice versa. We will test this by surgical placement of a passive constraining device around strengths of critical findings uncovered during the previous funding cycle and are in line with our overall objective of identifying the mechanisms of progressive deterioration of LV function that is characteristic of the HF state.